We originally showed that mice that inherit a Gnas exon 2 insertion paternally are leaner than normal and are hypermetabolic and hyperactive, while mice which inherit the mutation maternally become obese, hypometabolic, and hypoactive. Detailed metabolic studies have shown the paternal exon 2 knockout mice to have increased adiponectin and resistin expression in adipose tissue, increased whole body lipid metabolism, and increased insulin sensitivity in adipose tissue, muscle, and liver. We have created a new mouse line with flox sites around Gs-alpha exon 1, and with this have made mice with Gs-alpha specific deficiency. Heterozygous Gs-alpha-deficient mice develop obesity and insulin resistance, with the phenotype being more severe in maternal mice. These differences are presumably due to Gs-alpha imprinting, and this is supported by preliminary evidence that the paternal exon 1A deletion, which is known to be required for paternal Gs-alpha imprinting, can reverse the obesity resulting from maternal Gs-alpha deficiency. We also showed that mice with XL-alpha-s deficiency are severely lean and insulin sensitive, with increased sympathetic nervous system activity. This isoform presumably is a negative regulator of sympathetic nervous system activity, and XL-alpha-s deficiency is the cause of the paternal exon 2 deletion phenotype. We have also generated tissue-specific Gs-alpha knockouts in various metabolically active tissues. Liver-specific Gs-alpha deficiency leads to increased insulin sensitivity in multiple tissues, reduced adiposity, and maintenance of normal fasting blood sugars due to long-term breakdown of larger than normal glycogen stores. Preliminary results in fat- and muscle-specific Gs-alpha knockouts suggest important roles of this signaling molecule in glucose uptake, adaptive thermogenesis, and energy balance.